Identification of Novel Genetic Defects in Outbred Cone-Rod Dystrophy Patients Using Homozygosity Mapping

Abstract

Purpose: : To identify the causative gene-defects in patients with autosomal recessive cone-rod dystrophy (arCRD).

Methods: : Homozygosity mapping was performed with high-density SNP microarrays to identify new disease-causing genes and mutations. DNA samples of 27 arCRD patients from 11 non-consanguineous families and 42 isolated CRD-patients mostly from the Netherlands and Germany were analyzed for homozygous regions.

Results: : Initial analysis of the homozygosity data revealed the causative gene mutation in four families, including one known mutation in ABCA4, two novel mutations in genes known to cause a retinal dystrophy other than CRD (CABP4, PROM1) and one novel mutation in the newly identified gene EYS. Affected siblings shared one to three significant homozygous regions varying in size from 2 to 28 Mb. In two families, the causative mutations were found in the largest overlapping homozygous region, spanning 9 and 28 Mb, and in two families a mutation was identified in the second largest region, encompassing 5 and 10 Mb. We reevaluated the phenotype in patients carrying mutations in CABP4 and PROM1. In the sib pair with the PROM1 mutation we confirmed the diagnosis of CRD. Interestingly, in the sib pair with the CABP4 mutation, detailed characterization of the phenotype led to the description of a new phenotype, named congenital cone-rod synaptic disorder. Analysis of homozygous regions in the other families and isolated cases is ongoing.

Conclusions: : Using homozygosity mapping in CRD patients from outbred populations, we unraveled the molecular cause in at least 4 of 11 families, in one of which mutations were identified in the novel gene EYS. Furthermore, we show that molecular knowledge of the disease may lead to a better phenotypic understanding.

Keywords: gene mapping • retinal degenerations: hereditary